PNNL

Abstract

The activation of cell surface receptors in addition to initiating signaling events also triggers regulatory processes that restrict the duration of signaling. Acute attenuation of signaling can be accomplished either via ligand-induced internalization of receptors (receptor downregulation) or via ligand-induced receptor desensitization. These phenomena have traditionally been viewed in the context of “adaptation” wherein the receptor system enters a refractory state in the presence of sustained ligand stimuli and thereby prevents the cell from “over-responding” to the ligand. Here we use the epidermal growth factor receptor (EGFR) and G-protein coupled receptors (GPCR) as model systems to respectively examine the effects of downregulation and desensitization on the ability of signaling receptors to decode time-varying ligand stimuli. We show that downregulation and desensitization mechanisms can lead to tight and efficient input-output coupling thereby ensuring synchronous processing of ligand inputs. Frequency response analysis indicates that upstream elements of the EGFR and GPCR networks behave like low-pass filters. Receptor downregulation and desensitization increase the filter bandwidth thereby enabling the receptor systems to decode inputs in a wider frequency range. Further, system-theoretic analysis reveals that the receptor systems are analogous to classical mechanical over-damped oscillators. This analogy enables us to describe downregulation and desensitization as phenomena that make the systems more resilient in responding to ligand perturbations thereby improving the stability of the system resting state. We hypothesize that, in addition to serving as mechanisms for adaptation, receptor downregulation and desensitization play a critical role in temporal information processing.